The overall goal of this Project is to identify genetic determinants contributing to coronary artery disease (CAD) and its risk factors in outbred populations, with a particular emphasis on triglyceride and associated lipid metabolism. We propose to accomplish this by identifying the genes for lipid and lipoprotein variation in the major dyslipidemic disorder predisposing to atherosclerosis-familial combined hyperlipidemia (FCHL), by using the power of a systematic genome scan, augmented by findings from mouse-human synteny and allied human studies and culminating in the analyses of positional candidate genes. We will use these approaches to identify responsible genes and causative variations. This study capitalizes on a large and intensively studied collection of FCHL families, ascertained by Dr. Tierk de Bruin and colleagues, of the University of Maasstricht (The Netherlands). In the current cycle, we conducted linkage studies of a number of candidate genes. In addition we completed a 10 cM genome scan on 240 individuals in this FCHL family material. This work has led to the identification of possible regions for FCHL and its associated quantitative traits. The first Aim of this project is to extend the systematic 10 cM scan to our currently available study sample of 55 well characterized FCHL families comprising 1012 individuals, testing for linkage to both the quantitative trait of FCHL and its associated quantitative traits. (In parallel, additional families and individuals are being phenotyped by our collaborator, D. de Bruin). The second Aim is to fine map the 12 chromosomal regions have the best support for linkage, base don a multiple criteria: the lod scores, evidence for linkage in other studies (Project V in the Finns and/or mouse-human synteny), and co-incident mapping of quantitative traits. In order to select the loci having the best evidence for linkage, the third Aim is to test the loci identified in Aim 2 in 5 samples: the Finnish FCHL sample (Project V), and 4 CAD family populations, already collected by collaborating investigators Drs. Leslie Raffel (Los Angeles, Jonathan Cohen (Dallas), Ron Krauss (Berkeley) and their colleagues. The fourth is to test positional candidate genes in the areas with the best evidence for linkage as determined by Aims 1-3. This will be done by delineating the variants of the positional candidates, by sequencing selected individuals at the extremes of the phenotypes and with and without the linked markers. The variants will be tested for their effects on lipid and lipoprotein variations in the samples exhibiting linkage by the transmission disequilibrium test and genotype association approaches. Our long term goal for future cycles is to understand the manner in which these variations affect lipid variation and predispose to CAD, leading eventually to new therapies and preventive interventions.